Sanfilippo syndrome type B (mucopolysaccharidosis III B (MPS III-B)) is a rare autosomal recessive lysosomal storage disorder. Sanfilippo syndrome type B caused by deficiency of α-N-acetylglucosaminidase (NAGLU), one of the enzymes required for the lysosomal degradation of the glycosaminoglycan heparan sulfate. Heparan sulfate is normally found in the extracellular matrix and on cell surface glycoproteins. NAGLU degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. The enzyme deficiency leads to the accumulation of heparan sulfate in various organs. The incidence of Sanfilippo syndrome type B is about 0.4 per 100,000 births. Sanfilippo syndrome type B is biochemically characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. The disease initially manifests as aggressiveness and hyperactivity in humans between the ages of 2 and 6 years, later progressing to mental retardation and CNS degeneration, and ultimately death in early adulthood.
Sanfilippo syndrome type B displays wide clinical variability that is likely caused by a high degree of molecular heterogeneity of the NAGLU gene, with more than 100 different mutations in the naglu gene, ranging from small deletions and insertions to nonsense and missense mutations, that have been identified to date. Biochemical studies have confirmed the deleterious effects of many of these mutations (Yogalingam et al. (2001) Hum Mutat 18:264-281; Beesley et al. (2005) J Inherit Metab Dis 28:759-767; Beesley et al. (1998) J Med Genet 35:910-914; Emre et al. (2002) Hum Mutat 19:184-185; Tanaka et al. (2002) J Hum Genet 47:484-487; Tessitore et al. (2000) Hum Genet 107:568-576; Schmidtchen et al. (1998) Am J Hum Genet 62:64-69; Bunge et al. (1999) J Med Genet 36:28-31; Weber B, et al. (1999) Eur J Hum Genet 7:34-44, and referenced in Table 4). Despite having been cloned over ten years ago and having been studied for more than twenty years, no structural or mechanistic data for mammalian NAGLU have been obtained, hindering the development of potential therapeutic strategies to treat patients suffering from mucopolysaccharidosis III B (MPS III-B). Treatment today is largely supportive. There is currently no cure for Sanfilippo syndrome type B.